Structural and Volumetric Brain MRI Findings in Mild Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Routine MR imaging findings are frequently normal following mild traumatic brain injury and have a limited role in diagnosis and management. Advanced MR imaging can assist in detecting pathology and prognostication but is not readily available outside research settings. However, 3D isotropic sequences with ∼1-mm3 voxel size are available on community MR imaging scanners. Using such sequences, we compared radiologists' findings and quantified regional brain volumes between a mild traumatic brain injury cohort and non-brain-injured controls to describe structural imaging findings associated with mild traumatic brain injury. MATERIALS AND METHODS: Seventy-one military personnel with persistent symptoms and 75 controls underwent 3T MR imaging. Three neuroradiologists interpreted the scans using common data elements. FreeSurfer was used to quantify regional gray and white matter volumes. RESULTS: WM hyperintensities were seen in 81% of the brain-injured group versus 60% of healthy controls. The odds of ≥1 WM hyperintensity in the brain-injured group was about 3.5 times the odds for healthy controls (95% CI, 1.58-7.72; P = .002) after adjustment for age. A frontal lobe-only distribution of WM hyperintensities was more commonly seen in the mild traumatic brain injury cohort. Furthermore, 7 gray matter, 1 white matter, and 2 subcortical gray matter regions demonstrated decreased volumes in the brain-injured group after multiple-comparison correction. The mild traumatic brain injury cohort showed regional parenchymal volume loss. CONCLUSIONS: White matter findings are nonspecific and therefore a clinical challenge. Our results suggest that prior trauma should be considered in the differential diagnosis of multifocal white matter abnormalities with a clinical history of mild traumatic brain injury, particularly when a frontal predilection is observed.

Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology.

Children with an anxious temperament are prone to heightened shyness and behavioral inhibition (BI). When chronic and extreme, this anxious, inhibited phenotype is an important early-life risk factor for the development of anxiety disorders, depression and co-morbid substance abuse. Individuals with extreme anxious temperament often show persistent distress in the absence of immediate threat and this contextually inappropriate anxiety predicts future symptom development. Despite its clear clinical relevance, the neural circuitry governing the maladaptive persistence of anxiety remains unclear. Here, we used a well-established nonhuman primate model of childhood temperament and high-resolution 18fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to understand the neural systems governing persistent anxiety and to clarify their relevance to early-life phenotypic risk. We focused on BI, a core component of anxious temperament, because it affords the moment-by-moment temporal resolution needed to assess contextually appropriate and inappropriate anxiety. From a pool of 109 peri-adolescent rhesus monkeys, we formed groups characterized by high or low levels of BI, as indexed by freezing in response to an unfamiliar human intruder's profile. The high-BI group showed consistently elevated signs of anxiety and wariness across >2 years of assessments. At the time of brain imaging, 1.5 years after initial phenotyping, the high-BI group showed persistently elevated freezing during a 30-min 'recovery' period following an encounter with the intruder-more than an order of magnitude greater than the low-BI group-and this was associated with increased metabolism in the bed nucleus of the stria terminalis, a key component of the central extended amygdala. These observations provide a neurobiological framework for understanding the early phenotypic risk to develop anxiety-related psychopathology, for accelerating the development of improved interventions, and for understanding the origins of childhood temperament.

Serotonin transporter binding and genotype in the nonhuman primate brain using [C-11]DASB PET.

UNLABELLED: The length polymorphism of the serotonin (5-HT) transporter gene promoter region has been implicated in altered 5-HT function and, in turn, neuropsychiatric illnesses, such as anxiety and depression. The nonhuman primate has been used as a model to study anxiety-related mechanisms in humans based upon similarities in behavior and the presence of a similar 5-HT transporter gene polymorphism. Stressful and threatening contexts in the nonhuman primate model have revealed 5-HT transporter genotype dependent differences in regional glucose metabolism. Using the rhesus monkey, we examined the extent to which serotonin transporter genotype is associated with 5-HT transporter binding in brain regions implicated in emotion-related pathology. METHODS: Genotype data and high resolution PET scans were acquired in 29 rhesus (Macaca mulatta) monkeys. [C-11]DASB dynamic PET scans were acquired for 90 min in the anesthetized animals and images of distribution volume ratio (DVR) were created to serve as a metric of 5-HT transporter binding for group comparison based on a reference region method of analysis. Regional and voxelwise statistical analysis were performed with corrections for anatomical differences in gray matter probability, sex, age and radioligand mass. RESULTS: There were no significant differences when comparing l/l homozygotes with s-carriers in the regions of the brain implicated in anxiety and mood related illnesses (amygdala, striatum, thalamus, raphe nuclei, temporal and prefrontal cortex). There was a significant sex difference in 5-HT transporter binding in all regions with females having 18%-28% higher DVR than males. CONCLUSIONS: Because these findings are consistent with similar genotype findings in humans, this further strengthens the use of the rhesus model for studying anxiety-related neuropathologies.

The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor.

A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.

Neurobiology of depression: an integrated view of key findings.

AIMS: The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness. DISCUSSION: The present work reviews the evidence for the progressive nature of MDD along with associated changes in neuroanatomical structure and function, especially for the hippocampus. The role of glucocorticoids, inflammatory cytokines and brain-derived growth factors are discussed as mediators of these pathological alterations. From this integrated model, the role of antidepressant therapy in restoring normative processes is examined along with additional treatment guidelines. CONCLUSION: Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.

Aromatic L-amino acid decarboxylase turnover in vivo in rhesus macaque striatum: a microPET study.

The aromatic L-amino acid decarboxylase (AAAD) is involved in the de novo synthesis of dopamine, a neurotransmitter crucial in cognitive, neurobehavioral and motor functions. The goal of this study was to assess the in vivo turnover rate of AAAD enzyme protein in the rhesus macaque striatum by monitoring, using microPET imaging with the tracer [(18)F]fluoro-m-tyrosine (FMT), the recovery of enzyme activity after suicide inhibition. Results showed the AAAD turnover half-life to be about 86 h while total recovery was estimated to be 16 days after complete inhibition. Despite this relatively slow AAAD recovery, the animals displayed normal movement and behavior within 24 h. Based on the PET results, at 24 h, the animals have recovered about 20% of normal AAAD function. These findings show that normal movement and behavior do not depend on complete recovery of AAAD function but likely on pre-synaptic and post-synaptic compensatory mechanisms.

Comparison of fMRI motion correction software tools.

Motion correction of fMRI data is a widely used step prior to data analysis. In this study, a comparison of the motion correction tools provided by several leading fMRI analysis software packages was performed, including AFNI, AIR, BrainVoyager, FSL, and SPM2. Comparisons were performed using data from typical human studies as well as phantom data. The identical reconstruction, preprocessing, and analysis steps were used on every data set, except that motion correction was performed using various configurations from each software package. Each package was studied using default parameters, as well as parameters optimized for speed and accuracy. Forty subjects performed a Go/No-go task (an event-related design that investigates inhibitory motor response) and an N-back task (a block-design paradigm investigating working memory). The human data were analyzed by extracting a set of general linear model (GLM)-derived activation results and comparing the effect of motion correction on thresholded activation cluster size and maximum t value. In addition, a series of simulated phantom data sets were created with known activation locations, magnitudes, and realistic motion. Results from the phantom data indicate that AFNI and SPM2 yield the most accurate motion estimation parameters, while AFNI's interpolation algorithm introduces the least smoothing. AFNI is also the fastest of the packages tested. However, these advantages did not produce noticeably better activation results in motion-corrected data from typical human fMRI experiments. Although differences in performance between packages were apparent in the human data, no single software package produced dramatically better results than the others. The "accurate" parameters showed virtually no improvement in cluster t values compared to the standard parameters. While the "fast" parameters did not result in a substantial increase in speed, they did not degrade the cluster results very much either. The phantom and human data indicate that motion correction can be a valuable step in the data processing chain, yielding improvements of up to 20% in the magnitude and up to 100% in the cluster size of detected activations, but the choice of software package does not substantially affect this improvement.

Functional but not structural subgenual prefrontal cortex abnormalities in melancholia.

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.

Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms.

BACKGROUND: Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) -based morphometry studies of the hippocampus to date have produced mixed results. METHODS: In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects. RESULTS: No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory. CONCLUSIONS: Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.

Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis.

OBJECTIVE: The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG. METHOD: The authors recorded 28-channel EEG data for 18 unmedicated patients with major depression and 18 matched comparison subjects. Clinical outcome was assessed after nortriptyline treatment. Of the 18 depressed patients, 16 were considered responders 4-6 months after initial assessment. A median split was used to classify response, and the pretreatment EEG data of patients showing better (N=9) and worse (N=9) responses were analyzed with low-resolution electromagnetic tomography, a new method to compute three-dimensional cortical current density for given EEG frequency bands according to a Talairach brain atlas. RESULTS: The patients with better responses showed hyperactivity (higher theta activity) in the rostral anterior cingulate (Brodmann's area 24/32). Follow-up analyses demonstrated the specificity of this finding, which was not confounded by age or pretreatment depression severity. CONCLUSIONS: These results, based on electrophysiological imaging, not only support hemodynamic findings implicating activation of the anterior cingulate as a predictor of response in depression, but they also suggest that differential activity in the rostral anterior cingulate is associated with gradations of response.

Six-month test-retest reliability of MRI-defined PET measures of regional cerebral glucose metabolic rate in selected subcortical structures.

Test-retest reliability of resting regional cerebral metabolic rate of glucose (rCMR) was examined in selected subcortical structures: the amygdala, hippocampus, thalamus, and anterior caudate nucleus. Findings from previous studies examining reliability of rCMR suggest that rCMR in small subcortical structures may be more variable than in larger cortical regions. We chose to study these subcortical regions because of their particular interest to our laboratory in its investigations of the neurocircuitry of emotion and depression. Twelve normal subjects (seven female, mean age = 32.42 years, range 21-48 years) underwent two FDG-PET scans separated by approximately 6 months (mean = 25 weeks, range 17-35 weeks). A region-of-interest approach with PET-MRI coregistration was used for analysis of rCMR reliability. Good test-retest reliability was found in the left amygdala, right and left hippocampus, right and left thalamus, and right and left anterior caudate nucleus. However, rCMR in the right amygdala did not show good test-retest reliability. The implications of these data and their import for studies that include a repeat-test design are considered.

FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa.

OBJECTIVE: To evaluate the visible and quantitative anatomic distribution of fluorine-18-labeled L-DOPA in the healthy human brain, to thereby expand the understanding of extrastriatal sites of levodopa function, and to provide a broader foundation for clinical and research studies of fluoroDOPA accumulation in patients. METHODS: The authors performed dynamic three-dimensional fluoroDOPA PET imaging in 10 healthy volunteers and analyzed the images visually and quantitatively. Twenty-eight regions of interest were applied to parametric images of the uptake rate constant (using the multiple-time graphic plot method with cortical input function) and also were used to quantitate regional radioactivity at 80 to 90 minutes. The authors correlated the uptake constants with published human regional neurotransmitter and decarboxylation data. RESULTS: PET imaging with fluoroDOPA demonstrates trapping of labeled dopamine or its metabolites in substantial quantities in many areas of the brain other than the mesostriatal pathways, including considerable uptake in the serotonergic and noradrenergic areas of the hypothalamus and brainstem as well as in extrastriatal cerebral sites. Total fluoroDOPA uptake correlates best with the sum of catecholamine and indolamine concentrations in the brain and moderately well with regional activity of aromatic L-amino acid decarboxylase, but correlates poorly with extrastriatal dopamine concentration. CONCLUSION: Neither L-DOPA nor its radiolabeled analog fluoroDOPA is metabolized or accumulates specifically in dopaminergic or even catecholaminergic neurons. Substantial dopamine production within serotonin and norepinephrine neurons may play a role in either therapeutic effects or adverse effects of therapy with L-DOPA.

Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients.

BACKGROUND: EEG alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The hypothesis that the thalamus serves as a neuronal oscillator of alpha rhythms has been supported by studies in animals, but only minimally by studies in humans. METHODS: In the current study, PET-derived measures of regional glucose metabolism, EEG, and structural MRI were obtained from each participant to assess the relation between thalamic metabolic activity and alpha power in depressed patients and healthy controls. The thalamus was identified and drawn on each subject's MRI. The MRI was then co-registered to the corresponding PET scan and metabolic activity from the thalamus extracted. Thalamic activity was then correlated with a 30-min aggregated average of alpha EEG power. RESULTS: Robust inverse correlations were observed in the control data, indicating that greater thalamic metabolism is correlated with decreased alpha power. No relation was found in the depressed patient data. CONCLUSIONS: The results are discussed in the context of a possible abnormality in thalamocortical circuitry associated with depression.

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

Fluorine-18-fluoro-L-DOPA dosimetry with carbidopa pretreatment.

UNLABELLED: This article presents dosimetry based on the measurement of fluoro-DOPA activity in major tissues and in the bladder contents in humans after oral pretreatment with 100 mg carbidopa. METHODS: Bladder activity was measured continuously by external probe and calibrated using complete urine collections. Quantitative dynamic PET scans provided time-activity curves for the major organs. Bladder wall dosimetry was calculated using the methods of MIRD Pamphlet No. 14. Effective dose was calculated as described in ICRP Publication 60. RESULTS: Mean absorbed dose to the bladder wall surface per unit administered activity was 0.150 mGy/MBq (0.556 rad/mCi) with the realistic void schedule used in our studies. The dose was 0.027 mGy/MBq (0.101 rad/mCi) to the kidneys, 0.0197 mGy/MBq (0.0728 rad/mCi) to the pancreas, and 0.0186 mGy/MBq (0.0688 rad/mCi) to the uterus. Absorbed doses to other organs were an order of magnitude or more lower than the bladder, 0.009-0.015 mGy/MBq. The effective dose per unit administered activity was 0.0199 mSv/MBq (0.0735 rem/mCi.) CONCLUSION: Urinary excretion of fluoro-DOPA was altered significantly by pretreatment with carbidopa. In general, any manipulation of tracer metabolism in the body should be expected to produce changes in biodistribution and dosimetry. The largest radiation dose was to the bladder wall, for which our estimate was one-fifth of that from the original report. The methods used reflect realistic urinary physiology and typical use of this tracer. The principles of MIRD Pamphlet No. 14 should be used in planning studies using tracers excreted in the urine to minimize the absorbed dose.

A phantom study evaluating the quantitative aspect of 3D PET imaging of the brain.

Phantom studies are used to develop a reliable quantitative data processing protocol for 3D PET brain scanning for conditions typically encountered in FDG and neuroreceptor brain imaging. These protocols often span several half-lives of the injected radiotracer thus resulting in a greatly varying statistical content of the acquired data over the study duration. Detector normalization, scatter correction and their interplay over a wide range of statistical content of acquired data were evaluated. Overall sensitivity calibration factors were determined after all other quantification corrections were applied to the data. The result is an optimum data processing protocol that includes an iterative convolution subtraction scatter correction method, a normalization procedure that takes into account the geometric properties of the scanner and a region of interest based calibration procedure, applied in this order. This protocol yields a 3D PET quantification accuracy within approximately 3% of independently measured concentration values for scanning conditions that include variation in the number of acquired counts from one million to several hundred millions and variation in size and shape from a 20 cm diameter phantom to a tapered phantom with minimum cross section of 3.7 x 14.5 cm2. This performance is comparable with that of the 2D acquisition mode.

Quantitative comparison of three- and two-dimensional PET with human brain studies.

UNLABELLED: The aim of this study was to test the quantitation accuracy of three-dimensional PET in brain scanning. METHODS: Three-dimensional data from 11 human subjects were tested using 11C-dihydrotetrabenazine, 11C-Schering 23390 and 18F-FDG as tracers. Two-dimensional scans were performed on the same subjects and the distribution volume, distribution volume ratio and local metabolic rate of glucose (LMRGlu) values obtained from these were used as reference. Three-dimensional data were processed as follows: iterative convolution subtraction scatter correction, detector normalization including radial and axial geometric factors, attenuation correction extracted from a two-dimensional transmission scan, Kinahan-Rogers reconstruction and region-of-interest-based sensitivity calibration. RESULTS: No major systematic differences between the two methods were found. The agreement between the two-dimensional and three-dimensional data was within 5%. Although statistical analysis generally did not show this difference to be significant, reliability analysis indicated that comparing two-dimensional and three-dimensional data might introduce some inaccuracies. CONCLUSION: Three-dimensional PET yields quantitatively valid results for brain scanning.

Normalization for 3D PET with a low-scatter planar source and measured geometric factors.

For 3D PET normalization methods, a balance must be struck between statistical accuracy and individual detector or line-of-response (LOR) fidelity. Methods with potentially the best LOR accuracy tend to be statistically poor, while techniques to improve the statistical quality tend to reduce the individual detector fidelity. We have developed and implemented a 3D PET normalization method for our ECAT 953B scanner (Siemens/CTI) that determines the detector normalization factors (NFs) as a product of a four-dimensional matrix of measured geometric factors (GFs) and single detector efficiency factors (epsilon). The effects of various alterations to the algorithm on the accuracy of the normalization have been examined through the impact on reconstructed images. An accurate set of GFs is crucial, as inaccurate NFs can result if LORs with similar but not identical geometric symmetries are grouped together. The general method can be extended to other tomographs, although the dimensionality of a GF matrix may be scanner-specific; the key is to determine the optimal number of dimensions in the GF matrix. The GFs for our scanner are specified by: (i) the two detector rings for each LOR; (ii) the radial distance of the LOR from the tomograph centre; and (iii) the positions within the detector block of the two crystals defining the LOR. Some residual radial non-uniformities are present in all the NF variations we examined. For the NF method presented here, the radial non-uniformities are attributed to the interaction between object-dependent scatter and normalization. Results indicate that this non-uniformity is detectable for scans with as few as 13 million total counts.

Development of an improved target for [18F]F2 production.

An A1 body target with improved yields of electrophilic [18F]F2 on the Siemens/CTI 11 MeV proton cyclotron at Wisconsin has been developed. The saturation yield is 3.10 +/- 0.40 GBq/microA for beam currents up to 45 microA. The target has routinely produced 20-40 GBq of [18F]F2 for clinical and experimental use over 1600 microA-h operation, with a maximum yield to date of 45.5 GBq (1.2 Ci). Target design, performance and reliability are discussed.

Synthesis of the fluorine-18 labeled inhalation anesthetics.

Fourteen compounds (fluoroalkanes and fluoroethers), including the two most utilized inhalation anesthetics Isoflurane (CF3CHClOCF2H) and Halothane (CF3CHBrCl), have been labeled with fluorine-18 via a facile 18F-for-19F exchange reaction. The compounds include ten inhalation anesthetics which span a ten-fold range in potency and four structurally related non-anesthetics. All the compounds possess a trifluoromethyl group (CF3) adjoining a carbon atom with an acidic alpha-hydrogen and at least one halogen or a strong electron withdrawing group (X), [CF3CHXR]. We postulate the isotopic fluoride exchange reaction proceeds through a carbanion transition state resulting from alpha-proton transfer to base. The carbanion stability is attributed to the inductive effect of the CF3 group and the electron withdrawing capability of X. Compounds labeled in dimethyl sulfoxide (DMSO) at 125 degrees C in 15 min include Isoflurane-CF3CHClOCF2H (1) (97% [18F]fluorine incorporation, 99% radiochemical purity, respectively), Sevoflurane-CF3CHCF3OCFH2 (2) [98%, 99%], CF3CHBrOCF2H (3) [85%, 80%], Desflurane-CF3CHFOCF2H (4) [50%, 99%], Fluroxene-CF3CH2OCH = CH2 (5) [25%, 99%], Fluothyl-CF3CH2OCH2CF3 (6) [60%, 10% at a temperature of 175 degrees C], Halothane-CF3CHBrCl (7) [98%, 95%], CF3CH2I (8) [99%, 98%], CF3CH2Br (9) [18%, 98%], CF3CHCl2 (10) [95%, 98%], CF3CH2Cl (11) [90%, 20%], CF3CHClCF3 (12) [95%, 99%], (CF3)3CH (13) [99%, 99%] and HF-134a-CF3CFH2 (14) (15%, 93% at a temperature of 175 degrees C).